Evidence from patients with Alzheimer's disease suggests that the basal forebrain cholinergic system plays an important role in memory. In support of this proposal, we have found impaired visual recognition memory in macaques with lesions of the major nuclei of this system, and in normal monkeys administered the cholinergic muscarinic-receptor blocker scopolamine. Another form of retention, spatial memory, is also impaired by scopolamine, although it is more resistant than is recognition memory. Our results suggest, in addition, that scopolamine affects primary, not just secondary memory, and memory storage, not retrieval. Unlike scopolamine, which exerts maximal effects at delays of less than 3 seconds, tetrahydrocannabinol (THC) impairs stimulus memory only at delays exceeding 30 seconds. This suggests that THC is not exerting its effect via the cholinergic system and, indeed, using in vivo microdialysis in anesthetized monkeys, we found that THC increased acetylcholine release in the hippocampus on the first but not subsequent administrations, indicating that acetylcholine stores had not been depleted. Monkeys administered the dopaminergic-neurotoxin MPTP, who initially showed motor and habit formation impairments that resolved within a few weeks, were found later to be abnormally sensitive to the effects of scopolamine, suggesting residual damage to the dopaminergic system. This was confirmed by positron emission tomography and in vivo microdialysis, both of which showed reduced dopamine levels in caudate nucleus, putamen, and prefrontal cortex. The animals were subsequently found to have impaired detour reaching ability and spatial memory. In further tests of a neostriatal role in learning, we found that destruction of the visual system's neostriatal targets (i.e., tail of caudate nucleus and caudoventral putamen) produced severe impairment on a test of habit formation, but none in cognitive memory. To study the mechanisms involved in the reinforcing effects of drugs of abuse, we administered carbamazepine to monkeys self-administering cocaine and found that the former drug significantly decreased the daily intake of the latter.